Process for the synthesis of perindopril and pharmaceutically acceptable salts thereof.

ABSTRACT

Process for the industrial synthesis of perindopril of formula (I):  
                 
and pharmaceutically acceptable salts thereof.

The present invention relates to a process for the synthesis ofperindopril of formula (I):

and pharmaceutically acceptable salts thereof.

Perindopril and its pharmaceutically acceptable salts, and moreespecially its tert-butylamine salt, have valuable pharmacologicalproperties.

Their principal property is that of inhibiting angiotensin I convertingenzyme (or kininase II), which allows, on the one hand, prevention ofthe conversion of the decapeptide angiotensin I to the octapeptideangiotensin II (a vasoconstrictor) and, on the other hand, prevention ofthe degradation of bradykinin (a vasodilator) to an inactive peptide.

Those two actions contribute to the beneficial effects of perindopril incardiovascular diseases, more especially in arterial hypertension andheart failure.

Perindopril, its preparation and its use in therapeutics have beendescribed in European patent specification EP 0 049 658.

In view of the pharmaceutical value of this compound, it has beenimportant to be able to obtain it by an effective synthesis process,readily transposable to an industrial scale, that leads to perindoprilin a good yield and, especially, with excellent purity.

Patent specification EP 0 308 341 describes the industrial synthesis ofperindopril by the coupling of (2S,3aS,7aS)-octahydroindole-2-carboxylicacid benzyl ester with N-[(S)-1-carboxybutyl]-(S)-alanine ethyl ester inthe presence of dicyclohexylcarbodiimide, followed by deprotection ofthe carboxylic group of the heterocycle by catalytic hydrogenation.

That process has disadvantages related to use of thedicyclohexylcarbodiimide.

The Applicant has developed a process for the synthesis of perindoprilthat uses other coupling agents.

More specifically, the present invention relates to a process for thesynthesis of perindopril, which process is characterised in that thebenzyl ester of formula (IIa) or (IIb):

or an addition salt of the ester of formula (IIa) or (IIb) with amineral acid or organic acid is reactedwith the compound of formula (III):

in the presence of a coupling agent selected from the following reagentsand pairs of reagents:

-   (1,3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,-   (1,3-dimethylaminopropyl)-3-ethyl-carbodiimide    hydrochloride/1-hydroxybenzotriazole,-   (1,3-dimethylaminopropyl)-3-ethyl-carbodiimide    hydrochloride/1-hydroxy-7-azabenzo-triazole,-   (1,3-dimethylaminopropyl)-3-ethyl-carbodiimide    hydrochloride/N-hydroxysuccinimide,-   (1,3-dimethylaminopropyl)-3-ethyl-carbodiimide    hydrochloride/3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine,-   (1,3-dimethylaminopropyl)-3-ethyl-carbodiimide    hydrochloride/N-hydroxyphthalimide,-   dicyclohexylcarbodiimide/1-hydroxy-7-azabenzotriazole,-   dicyclohexylcarbodiimide/N-hydroxysuccinimide,-   dicyclohexylcarbodiimide/3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine,-   dicyclohexylcarbodiimide/N-hydroxyphthalimide,-   O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate,-   O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate,-   O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate,-   benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate,-   benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium    hexafluorophosphate,-   O-(benzotriazol-1-yl)-1,1,3,3-bis(tetramethylene)uronium    hexafluorophosphate,-   O-(benzotriazol-1-yl)-1,1,3,3-bis(pentamethylene)uronium    hexafluorophosphate,-   chloro-tripyrrolidinophosphonium hexafluorophosphate,-   chloro-1,1,3,3-bis(tetramethylene)formamidinium hexafluorophosphate,-   chloro-1,1,3,3-bis(pentamethylene)formamidinium hexafluorophosphate,-   N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline,-   O-[(ethoxycarbonyl)-cyanomethyleneamino]-1,1,3,3-tetramethyluronium    tetrafluoroborate,-   O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluronium    tetrafluoroborate,-   O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluronium    tetrafluoroborate/1-hydroxybenzotriazole,-   O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluronium    tetrafluoroborate/N-methylmorpholine,-   O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluronium    tetrafluoroborate/collidine,-   O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-tetramethyluronium    tetrafluoroborate,-   O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-tetramethyluronium    tetrafluoroborate/1-hydroxybenzotriazole,-   O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-bis(tetramethylene)uronium    hexafluorophosphate,-   O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-bis(tetramethylene)uronium    hexafluoro-phosphate/1-hydroxy-benzotriazole,-   O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate,-   O-(N-succinimidyl)-1,1,3,3-bis(tetramethylene)uronium    tetrafluoroborate,-   O-(N-succinimidyl)-1,1,3,3-bis(tetramethylene)uronium    tetrafluoroborate/1-hydroxy-benzotriazole,-   O-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium    tetrafluoroborate,-   propanephosphonic anhydride,-   N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide, and    N-hydroxy-1,2-dihydro-2-oxo-pyridine,    optionally in the presence of a base,    to yield, after catalytic hydrogenation in the presence of    palladium, perindopril of formula (I), which is converted, if    desired, into a pharmaceutically acceptable salt such as the    tert-butylamine salt.

When the compound of formula (IIa) is used as starting material, thecatalytic hydrogenation is preferably carried out under a hydrogenpressure of less than 10 bars.

When the compound of formula (IIb) is used as starting material, thecatalytic hydrogenation is preferably carried out under a hydrogenpressure of from 10 to 35 bars.

The example hereinbelow illustrates the invention.

EXAMPLE 1 Benzyl(2S,3aS,7aS)-1-{((2S)-2-[(1S)-1-(ethoxycarbonyl)-butylamino]-propionyl}-octahydro-1H-indole-2-carboxylate

200 g of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid benzyl esterpara-toluene-sulphonate, 65 ml of triethylamine and 1 litre of ethylacetate are introduced into a stirred reactor, followed, after stirringfor 10 minutes at ambient temperature, by 100 g ofN-[(S)-ethoxycarbonyl-1-butyl]-(S)-alanine and 175 g ofO-(benzotriazol-1-yl)-1,1,3,3-bis(tetra-methylene)uroniumhexafluorophosphate. The heterogeneous mixture is then heated at 30° C.for 3 hours whilst stirring well and is then cooled to 0° C. andfiltered.

The filtrate is then washed and subsequently evaporated to dryness toyield the expected product.

EXAMPLE 2(2S,3aS,7aS)-1-{(2S)-2-[(1S)-1-(Ethoxycarbonyl)-butylamino]-propionyl}-octahydro-1H-indole-2-carboxylicacid

The residue obtained in the previous step (200 g) is dissolved in 200 mlof methyl-cyclohexane and transferred to a hydrogenator; 26 g of 5%palladium-on-carbon suspended in 80 ml of methylcyclohexane are thenadded, followed by 640 ml of water.

The mixture is then hydrogenated under a pressure of 0.5 bar at atemperature of from 15 to 30° C., until the theoretical amount ofhydrogen has been absorbed.

After filtering off the catalyst, the aqueous phase of the filtrate iswashed with methylcyclohexane and then lyophilised to yield the expectedproduct in a yield of 94%.

EXAMPLE 3(2S,3aS,7aS)-1-{(2S)-2-[(1S)-(Ethoxycarbonyl)-butylamino]-propionyl}-octahydro-1H-indole-2-carboxylicacid tert-butylamine salt

The lyophilisate obtained in the previous step (200 g) is dissolved in2.8 litres of ethyl acetate, and then 44 g of tert-butylamine and 400 mlof ethyl acetate are added.

The suspension obtained is then refluxed until dissolution is complete;then the solution obtained is filtered whilst hot and cooled to atemperature of 15-20° C., with stirring.

The precipitate obtained is then filtered off, made into a paste againusing ethyl acetate, dried and then ground to yield the expected productin a yield of 95%.

1-6. (canceled)
 7. A process for the industrial synthesis of perindoprilof formula (I)

and pharmaceutically acceptable salts thereof, wherein a benzyl ester offormula (IIa) or (IIb):

or an addition salt of the ester of formula (IIa) or (IIb) with amineral acid or organic acid, is reacted with a compound of formula(III):

in the presence of a coupling agent selected from:(1,3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride,(1,3-dimethylaminopropyl)-3-ethyl-carbodiimidehydrochloride/1-hydroxybenzotriazole,(1,3-dimethylaminopropyl)-3-ethyl-carbodiimidehydrochloride/1-hydroxy-7-azabenzo-triazole,(1,3-dimethylaminopropyl)-3-ethyl-carbodiimidehydrochloride/N-hydroxysuccinimide,(1,3-dimethylaminopropyl)-3-ethyl-carbodiimidehydrochloride/3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine,(1,3-dimethylaminopropyl)-3-ethyl-carbodiimidehydrochloride/N-hydroxyphthalimide,dicyclohexylcarbodiimide/1-hydroxy-7-azabenzotriazole,dicyclohexylcarbodiimide/N-hydroxysuccinimide,dicyclohexylcarbodiimide/3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine,dicyclohexylcarbodiimide/N-hydroxyphthalimide,O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate,O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate, O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate, benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate,benzotriazol-1-yl-oxy-tris(dimethylamino)phosphoniumhexafluorophosphate,O-(benzotriazol-1-yl)-1,1,3,3-bis(tetramethylene)uroniumhexafluorophosphate,O-(benzotriazol-1-yl)-1,1,3,3-bis(pentamethylene)uroniumhexafluorophosphate, chloro-tripyrrolidinophosphoniumhexafluorophosphate, chloro-1,1,3,3-bis(tetramethylene)formamidiniumhexafluorophosphate, chloro-1,1,3,3-bis(pentamethylene)formamidiniumhexafluorophosphate, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline,O-[(ethoxycarbonyl)-cyanomethyleneamino]-1,1,3,3-tetramethyluroniumtetrafluoroborate,O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate,O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate/1-hydroxybenzotriazole,O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate/N-methylmorpholine,O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate/collidine,O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate,O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate/1-hydroxybenzotriazole,O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-bis(tetramethylene)uroniumhexafluorophosphate,O-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-bis(tetramethylene)uroniumhexafluoro-phosphate/1-hydroxy-benzotriazole,O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate,O-(N-succinimidyl)-1,1,3,3-bis(tetramethylene)uronium tetrafluoroborate,O-(N-succinimidyl)-1,1,3,3-bis(tetramethylene)uroniumtetrafluoroborate/1-hydroxy-benzotriazole,O-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluroniumtetrafluoroborate, propanephosphonic anhydride,N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide, andN-hydroxy-1,2-dihydro-2-oxo-pyridine, optionally in the presence of abase, to yield, after catalytic hydrogenation in the presence ofpalladium, perindopril of formula (I), which is converted, if desired,into a pharmaceutically acceptable salt.
 8. The process of claim 7 forthe synthesis of perindopril in the form of its tert-butylamine salt. 9.The process of claim 7, wherein the compound of formula (IIa) is used asstarting material.
 10. The process of claim 7, wherein the compound offormula (IIb) is used as starting material.
 11. The process of claim 9,wherein the hydrogenation reaction is carried out under a hydrogenpressure of less than 10 bars.
 12. The process of claim 10, wherein thehydrogenation reaction is carried out under a hydrogen pressure of from10 to 35 bars.